The pathology of traumatic brain injury in experimental models includes acute inflammatory reaction, blood brain barrier disruption, hemorrhage, demyelination, axonal transection and chronically with axonal neuronal loss and gliosis. Stem cell (SC) therapy is a potential treatment either as replacement therapy or via paracrine effect with release of growth factors and anti-inflammatory cytokines for TBI injury. Experimental studies in rodent models of TBI have been limited and usually a single dose of cells is administered within 24 to 72 hours after experimental injury. The optimal timing and dose of cell delivery to maximize functional recovery and transplantation survival during the acute inflammatory and edematous phase of damage is unknown. We evaluated the natural history of control cortical impact (CCI) to induce TBI in the rat brain by serial MRI, molecular biological and histological analysis. We reported that the efficacy of multiple intravenous or intracardiac administrations of rat mesenchymal stromal cells or human mesenchymal stromal cells in female rats after controlled cortical impact by in vivo MRI, neurobehavior, and histopathology evaluation. Neither intravenous nor intracardiac administration of mesenchymal stromal cells derived from either rats or humans improved MRI measures of lesion volume or neurobehavioral outcome compared to saline treatment. Few mesenchymal stromal cells (<0.0005% of injected dose) were found within 3 days of last dosage at the site of injury after either delivery route, with no mesenchymal stromal cells being detectable in brain at 30 or 56 days post-injury. These findings suggest that non-autologous mesenchymal stromal cells therapy via intravenous or intracardiac administration is not a promising treatment after focal contusion traumatic brain injury in this female rodent model. We reported on a longitudinal study in a mild TBI rat model based on MRI and correlated to histology over 2 months. We reported that diffusion tensor imaging (DTI) axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. We also observed that FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity and magnetization transfer ratio (MTR) demonstrated a strong correlation with both axon and myelin integrity. We also were able to demonstrate that in rats with mild ventriculomegaly (MVM) demonstrated insignificant changes in FA, suggesting less axonal injury compared to normal rats following mild TBI. The MVM animals had significant increase in MTR compared to normal rats following mild TBI. On histological examination, limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brains compared with normal animals. MVM rats exhibited greater inflammation following TBI compared to normal rat brains. These results indicated the importance of using MRI to screen for brain abnormalities in experimental animals used in TBI studies and that the variation observed in TBI studies may be due to the variability in response to induced trauma as a result of structural morphology.